Scientists at the University of Michigan Rogel Cancer Center discovered a small molecule that blocks a key pathway for brain tumours. The problem was how to get the inhibitor into the brain and to the tumour.
Collaboration with many labs allowed the team to fabricate a nanoparticle to hold the inhibitor. The results were even better than anticipated.
The nanoparticles delivered the inhibitor to the tumour in mice models. This drug turned on the immune system to eradicate cancer. A reintroduced tumor was also removed. This is a sign that this new approach may not only be able to treat brain tumours, but could also prevent or delay future recurrences.
“No one could get that molecule into the brain. This is a significant milestone. Maria G. Castro, Ph.D. R.C. stated that the outcomes for patients with glioma are not improving over the past 30 years. Schneider Collegiate Professor in Neurosurgery at Michigan Medicine. Castro is the senior author. The study was published in ACS Nano.
“Despite many types of cancer having seen survival gains, glioma is still a difficult disease with only 5% of patients surviving five years,” said Pedro R. Lowenstein M.D., Ph.D. Richard C. Schneider Professor of Neurosurgery at Michigan Medicine.
Gliomas can be resistant to conventional therapies. The tumour environment suppresses the immune system making new immuno-based therapies uneffective. These tumours are even more difficult to treat because they must pass the blood brain barrier.
Castro-Lowenstein saw an opportunity. AMD3100, a small-molecule inhibitor, was created to block CXCR12’s action. This cytokine is released by glioma cells and builds up a shield around immune system. It prevents it from attacking invading tumors. In mouse models of glioma, researchers found that AMD3100 blocked CXCR12 binding to immune-suppressive myeloid cell lines. These cells can be disarmed so that the immune system is able to attack tumour cells.
AMD3100 was having difficulty reaching the tumour. The drug was not able to travel well through the bloodstream. It also did not cross the blood brain barrier. This is an important issue when trying to get drugs into the brain.
Castro-Lowenstein Lab collaborated with Joerg Lehann, Ph.D. Wolfgang Pauli College Professor of Chemical Engineering at U-M College of Engineering in order to create protein-based particles to encapsulate and pass the inhibitor through the bloodstream.
Castro also met with Anuska V.Andjelkovic (M.D.), Ph.D., who is a professor of pathology at Michigan Medicine and research professor in neurosurgery whose research focuses upon the blood-brain barrier. They also noted that glioma tumors can cause abnormal blood vessels which interfere with normal blood flow.
Researchers injected nanoparticles containing AMD3100-loaded AMD3100-loaded particles into mice with gliomas. The surface of the nanoparticles contained an peptide that binds with a protein most commonly found in brain tumour cells. The nanoparticles traveled through the bloodstream towards the tumour and released AMD3100. This restored blood vessel integrity. Once the nanoparticles reached their target, they released the drug. This prevented the immune-suppressive meeloid cells from entering the tumour mass. This enabled the immune system to delay the growth of the tumor and kill it.
“If there isn’t enough blood flow, nothing can get to your target. This is why tumours are so intelligent. Castro stated that AMD3100 repairs the conduits and allows nanoparticles into the tumour.
Further research in mice and on patient cell lines showed that the combination of the AMD3100 Nanoparticle and radiation therapy increased the effectiveness beyond the radiation or nanoparticle alone.
The researchers then replicated a recurrence by reintroducing the tumour to mice with removed tumours. 60% of mice remained healthy without the need for additional therapy. AMD3100, which acts as a vaccine, created immune memory that allows the immune system recognize and destroy reintroduced cells. Castro stated that while it prevented recurrences from mice, it was good for people.
“Every glioma recurs. Castro stated that it is very important for glioma therapies to have this immune memory. Initial tests revealed that treatment had minimal to no effect on the liver, kidney, or heart function. The mice also showed normal blood counts after treatment. The base of the nanoparticle is similar to those that have been tested in humans previously and has been proven safe. Before moving on to clinical trials, additional safety testing will be required.